DESCRIPTION: (provided by the applicant) This application is written in response to the Program Announcement entitled, "Cutting Edge Basic Research Awards" (PA #: PAR-01-047) designed to foster 'high-risk and potentially high-impact' research that will 'advance our understanding of drug abuse and addiction'. The PI has completed a number of electrophysiological recording experiments in behaving rats to investigate underlying cellular mechanisms mediating the reinforcing properties of cocaine as well as 'natural' (water/food) reinforcement. One advantage of this approach is that it enables the characterization of nucleus accumbens (Acb) cell firing at critical times during goal-directed behaviors. For example, the PI and others have shown that a subset of Acb neurons appear to encode the 'critical' features of drug or appetitive reinforced responding including response initiation, response execution and reinforcement delivery (e.g. Bowman, et al., 1996; Schultz et al., 1992, Carelli and Deadwyler, 1994, 1997; Carelli et al., 2000; Peoples et al., 1997, 1998; Chang et al., 1994, 1998). However, one disadvantage of this approach is that the role of dopamine (DA) in reward-related processing can only be indirectly inferred in electrophysiology experiments. In contrast, fast scan cyclic voltammetry can be used to directly measure DA in the Acb on a millisecond time scale with micron spatial resolution that provides chemical information analogous to that obtained from electrophysiological unit recording. In this regard, the PI is currently working in collaboration with Dr. Mark Wightman, an analytical chemist and pioneer in the development and application of this technique in behaving animals, to examine changes in DA efflux in the Acb during cocaine self-administration sessions in rats. The purpose of this proposal is to expand those studies and to measure changes in Acb cell firing and Acb dopamine from the same electrode in behaving rats. Specifically, Aim 1 will develop the technology for combined electrophysiological recording and voltammetric measurements of DA in the Acb from the same electrode in awake rats. Aim 2 will expand that study and apply this technology to examine Acb cell firing and corresponding changes in DA levels in the Acb during cocaine self-administration sessions in rats. This combined electrophysiology/voltammetry approach will provide the first unique view of real-time, spatially resolved concentration fluctuations of DA in conjunction with changes in cell firing in the Acb during goal-directed behaviors. As such, we will be able to directly examine the contribution of DA in mediating underlying cellular mechanisms in the Acb that are involved in encoding information related to cocaine reinforcement.